NF-κB System Is Chronically Activated and Promotes Glomerular Injury in Experimental Type 1 Diabetic Kidney Disease

• Published in: Frontiers in physiology Vol. 11; p. 84
• Main Authors: Foresto-Neto, Orestes, Albino, Amanda Helen, Arias, Simone Costa Alarcon, Faustino, Viviane Dias, Zambom, Fernanda Florencia Fregnan, Cenedeze, Marcos Antonio, Elias, Rosilene Motta, Malheiros, Denise Maria Avancini Costa, Camara, Niels Olsen Saraiva, Fujihara, Clarice Kazue, Zatz, Roberto
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11-02-2020
• Subjects: diabetic kidney disease; glomerulosclerosis; innate immunity; NF-κB; Physiology; pyrrolidine dithiocarbamate; diabetic kidney disease; NF-κB; glomerulosclerosis; innate immunity; pyrrolidine dithiocarbamate
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2020.00084

High glucose concentration can activate TLR4 and NF-κB, triggering the production of proinflammatory mediators. We investigated whether the NF-κB pathway is involved in the pathogenesis and progression of experimental diabetic kidney disease (DKD) in a model of long-term type 1 diabetes mellitus (DM). Adult male Munich-Wistar rats underwent DM by a single streptozotocin injection, and were kept moderately hyperglycemic by daily insulin injections. After 12 months, two subgroups - progressors and non-progressors - could be formed based on the degree of glomerulosclerosis. Only progressors exhibited renal TLR4, NF-κB and IL-6 activation. This scenario was already present in rats with short-term DM (2 months), at a time when no overt glomerulosclerosis can be detected. Chronic treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented activation of renal TLR4, NF-κB or IL-6, without interfering with blood glucose. PDTC prevented the development of glomerular injury/inflammation and oxidative stress in DM rats. In addition, the NF-κB p65 component was detected in sclerotic glomeruli and inflamed interstitial areas in biopsy material from patients with type 1 DM. These observations indicate that the renal NF-κB pathway plays a key role in the development and progression of experimental DKD, and can become an important therapeutic target in the quest to prevent the progression of human DKD.